U.S. patent application number 11/994017 was filed with the patent office on 2008-08-21 for amine oxidase inhibitors.
Invention is credited to Lawrence M. Sayre.
Application Number | 20080199933 11/994017 |
Document ID | / |
Family ID | 37605097 |
Filed Date | 2008-08-21 |
United States Patent
Application |
20080199933 |
Kind Code |
A1 |
Sayre; Lawrence M. |
August 21, 2008 |
Amine Oxidase Inhibitors
Abstract
A therapeutic agent for selectively inhibiting amine oxidases
associated diseases and conditions in humans includes at least one
compound selected from the group consisting of propargylamines,
polypropargylamines, homopropargylamines,
4-substituted-2-butynylamines, 2- and 3-halloallylamines, pyrroline
derivatives, cycloalkenyl branched primary amines, propargyl
diamines, homopropargyl amines and diamines, allenyl amines and
diamines, chloroallyl diamines, lysyne analogues,
.beta.-haloamines, RF-substituted amines, RC.sub.1-substituted
amines, and R3Si substituted amines.
Inventors: |
Sayre; Lawrence M.;
(Cleveland, OH) |
Correspondence
Address: |
TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP
1300 EAST NINTH STREET, SUITE 1700
CLEVELAND
OH
44114
US
|
Family ID: |
37605097 |
Appl. No.: |
11/994017 |
Filed: |
June 30, 2006 |
PCT Filed: |
June 30, 2006 |
PCT NO: |
PCT/US06/25823 |
371 Date: |
December 27, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60695950 |
Jul 1, 2005 |
|
|
|
Current U.S.
Class: |
435/184 |
Current CPC
Class: |
A61K 31/137
20130101 |
Class at
Publication: |
435/184 |
International
Class: |
C12N 9/99 20060101
C12N009/99 |
Goverment Interests
GOVERNMENT RIGHTS
[0002] The invention described in this application was supported,
at least in part, by United Stated Government Contract No. NIH
Grant No. GM48812 with the National Institutes of Health.
Claims
1. A method of inhibiting quinone-dependent copper amine oxidases,
comprising contacting the quinone dependent copper amine oxidase
with an inhibitory amount of a compound selected from the group
consisting of: ##STR00054## where m and n are each independently 1,
2, or 3; X.sub.1 is selected from the group consisting of 0, S, and
C(.dbd.O)NH; X.sub.4 is a halo; and R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10,
R.sub.11, R.sub.12, R.sub.13, R.sub.14, Y.sub.1, and X.sub.2 are
each individually selected from the group consisting of hydrogen,
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, C.sub.2-C.sub.24
alkynyl, C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl,
C.sub.6-C.sub.24 aralkyl, substituted aryl, substituted alkyl,
halo, hydroxyl, sulfhydryl, C.sub.1-C.sub.24 alkoxy,
C.sub.2-C.sub.24 alkenyloxy, C.sub.2-C.sub.24 alkynyloxy,
C.sub.5-C.sub.20 aryloxy, acyl (including C.sub.2-C.sub.24
alkylcarbonyl (--CO-alkyl) and C.sub.6-C.sub.20 arylcarbonyl
(--CO-aryl)), acyloxy (--O-acyl), C.sub.2-C.sub.24 alkoxycarbonyl
(--(CO)--O-alkyl), C.sub.6-C.sub.20 aryloxycarbonyl
(--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl,
arylsulfanyl, C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof; or
a pharmaceutically acceptable salt thereof.
2. The method of claim 1, the compound comprising a propargylamine
selected from the group consisting of: ##STR00055##
3. The method of claim 1, the compound comprising a conjugated
propargylamine selected from the group consisting of:
##STR00056##
4. The method of claim 1, the compound comprising a trialkylsilyl
substituted propargylamine selected from the group consisting of:
##STR00057##
5. The method of claim 1, the compound comprising a
polypropargylamine selected from the group consisting of:
##STR00058##
6. The method of claim 1, the compound comprising a
homopropargylamine selected from the group consisting of:
##STR00059##
7. The method of claim 1, the compound comprising a
4-R6X1-substituted 2-butynylamine selected from the group
consisting of: ##STR00060##
8. The method of claim 1, the compound comprising a
4-R6X1-substituted 2-butynylamine selected from the group
consisting of: ##STR00061##
9. The method of claim 1, the compound comprising a
3-cholorallylamine selected from the group consisting of:
##STR00062##
10. The method of claim 1, the compound comprising a
3-cholroallylamine selected from the group consisting of:
##STR00063##
11. The method of claim 1, the compound comprising a
3-haloallylamine selected from the group consisting of:
##STR00064##
12. The method of claim 1, the compound comprising a
3-bromo-2-methylallylamine selected from the group consisting of:
##STR00065##
13. The method of claim 1, the compound comprising a
2-chloroallylamine selected from the group consisting of:
##STR00066##
14. The method of claim 1, the compound comprising a allenyl amine
selected from the group consisting of: ##STR00067##
15. The method of claim 1, the compound comprising a pyrolline
selected from the group consisting of: ##STR00068##
16. The method of claim 1, the compound comprising a chlorinated
homoallylamine selected from the group consisting of:
##STR00069##
17. The method of claim 1, the compound comprising an amine
selected from the group consisting of: ##STR00070##
18. The method of claim 1, the compound comprising a diamine
selected from the group consisting of: ##STR00071##
19. The method of claim 1, the compound comprising a lysyne analog
selected from the group consisting of: ##STR00072##
20. The method of claim 1, the compound comprising a beta-haloamine
selected from the group consisting of: ##STR00073##
21. The method of claim 1, the compound comprising a substituted
amine selected from the group consisting of: ##STR00074##
22. A therapeutic agent for selectively inhibiting
quinone-dependent copper amine oxidases, comprising contacting the
quinone dependent copper amine oxidase with an inhibitory amount of
a compound selected from the group consisting of: ##STR00075##
where m and n are each independently 1, 2, or 3; X.sub.1 is
selected from the group consisting of O, S, and C(.dbd.O)NH;
X.sub.4 is a halide; and R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11,
R.sub.12, R.sub.13, R.sub.14, Y.sub.1, and X.sub.2 are each
individually selected from the group consisting of hydrogen,
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, C.sub.2-C.sub.24
alkynyl, C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl,
C.sub.6-C.sub.24 aralkyl, substituted aryl, substituted alkyl,
halo, hydroxyl, sulfhydryl, C.sub.1-C.sub.24 alkoxy,
C.sub.2-C.sub.24 alkenyloxy, C.sub.2-C.sub.24 alkynyloxy,
C.sub.5-C.sub.20 aryloxy, acyl (including C.sub.2-C.sub.24
alkylcarbonyl (--CO-alkyl) and C.sub.6-C.sub.20 arylcarbonyl
(--CO-aryl)), acyloxy (--O-acyl), C.sub.2-C.sub.24 alkoxycarbonyl
(--(CO)--O-alkyl), C.sub.6-C.sub.20 aryloxycarbonyl
(--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl,
arylsulfanyl, C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof; or
a pharmaceutically acceptable salt thereof.
Description
RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. US 60/695,950, filed Jul. 1, 2005, which is herein
incorporated by reference it its entirety.
TECHNICAL FIELD
[0003] The present application relates to copper amine oxidase
inhibitors and to methods of using such inhibitors for therapeutic
applications.
BACKGROUND
[0004] There are now known to be three human genes that code for
the TPQ-containing amine oxidases, AOC.sub.1, AOC.sub.2, and
AOC.sub.3.
[0005] AOC.sub.1 is the diamine oxidase found primarily in kidney
(HKDAO), though it is also expressed in the liver and brain. The
enzyme is thought to be involved in the catabolism of histamine and
of putrescine and other polyamines, important mediators of nuclear
events underlying cell proliferation. This suggests a fundamental
role of HKDAO in the regulation of growth. At the same time, the
H.sub.2O.sub.2 and aldehydes resulting from polyamine metabolism
have been suggested to contribute to apoptotic cell death in brain
injury. The presence of DAO at the interface between rapidly
dividing (e.g., epithelial) and quiescent cells suggests that it
might be involved in regulating cell division or differentiation at
tissue boundaries. Involvement of DAO in the metabolism of
histamine implicates its role in the progression of
inflammation.
[0006] AOC.sub.2 is the retina-specific amine oxidase. The function
is not yet clear, and there have been no suggestions in the prior
art of a possible therapeutic effect of having a specific inhibitor
of this enzyme.
[0007] AOC.sub.3 codes for an amine oxidase, which is also the
human vascular adhesion protein (HVAP-1), responsible for the
binding of lymphocytes to the endothelial cell surface and the
promotion of their transendothelial migration. A number of studies
point to this enzyme being a useful anti-inflammatory target.
Further, since leukocyte migration from the blood to tissues is a
prerequisite for normal immune responses, inhibitors of HVAP-1 will
be important for modulating the immune response. This enzyme,
responsible for the semicarbazide-sensitive amine oxidase (SSAO)
activity in mammalian tissues, is largely associated with the
plasma membrane of various tissues, and is particularly high in
vascular and nonvascular smooth muscle cells, but is also found in
other cell types such as adipocytes, chondrocytes, and
odontoblasts. There are several pathological states where increased
circulating SSAO activity has been found: diabetes mellitus,
congestive heart failure, cerebral infarction, uremia, inflammatory
liver diseases (e.g., cirrhosis), obesity, and hyperlipidemia. High
levels of SSAO are also found in atherosclerotic plaques, and serum
SSAO activity correlates with the severity of atherosclerosis, as
well as intima-media thickness and serum cholesterol levels. It has
been proposed that vascular SSAO is involved in the regulation of
vascular tone, and thus vascular SSAO inhibition may offer a novel
mechanism of vasodilation.
[0008] The role of SSAO in the pathophysiology of diabetes has been
most extensively investigated. Elevated SSAO activity is associated
with type 1 diabetes already at first clinical diagnosis, and in
type 2 diabetes, particularly in diabetic patients with vascular
complications, such as retinopathy and arteriosclerosis. It has
therefore been speculated that SSAO may contribute to the
development of vascular complications associated with diabetes.
SSAO is associated with translocation of the glucose transporter
GLUT4 into the adipose cell surface and thereby promotes glucose
uptake in adipose tissue and smooth muscle cells. SSAO contributes
to elevated formation of cytotoxic metabolites (principally
methylglyoxal from aminoacetone, formaldehyde from methylamine, and
H.sub.2O.sub.2 as by-product) that exacerbate advanced glycation of
proteins (including crosslinking) and cause endothelial injury of
blood vessels, resulting in early development of atherosclerosis
and late-stage diabetic complications such as neuropathy,
retinopathy, and nepropathy. Thus SSAO inhibitors may be
ameliorative in the development of atherosclerosis and diabetic
complications. Plasma SSAO activity is elevated in morbidly obese
patients, which might contribute to the increased cardiovascular
risk associated with obesity. A potent, selective SSAO inhibitor
was found to reduce atherogenesis in a genetically obese diabetic
mouse strain fed a high cholesterol diet. Furthermore, a recent
study showed that an antibody to block VAP-1 in mice prevented
diabetes in a subset of nonobese diabetic mice. Interestingly,
aminoguanidine, which blocks advanced glycation and reduces
nephropathy in animals, is more potent at inhibiting SSAO than its
affect on glycation.
[0009] In addition to the LTQ-containing lysyl oxidase (LOX), human
genes for four LOX-like proteins have been recently identified:
LOXL, LOXL2, LOXL3 and LOXL4. In most tissues, LOX is responsible
for the lysine-derived cross-links in collagen and elastin, which
is the essential step for biogenesis and repair of the fibrillar
extracellular matrix. Despite what should be a harmful effect of
lysyl oxidase inhibition early in life, there is growing evidence
that the enzyme also plays a role in late-onset fibrotic conditions
in man.
SUMMARY
[0010] The present invention relates to a method of inhibiting
quinone-dependent copper amine oxidases. In the method, the quinone
dependent copper amine oxidase is contacted with an inhibitory
amount of a compound selected from the group consisting of
propargylamines, such as simple propargylamines, triple bond
conjugated propargylamines, trialkylsilyl substituted
propargylamines, polypropargylamines, homopropargylamines,
4-substituted-2-butynylamine, 2- and 3-halloallylamines, such as
3-chloroallylamines, 3-(alkoxycarbonyl)-3-chloroallylamines, 2- and
3-aryl-3-haloallylamines, 2-halo-3-arylallylamines,
3-haloo-2-methylallylamines, 2-haloallylamines, pyrroline
derivatives, cycloalkenyl branched primary amines, propargyl
diamines, homopropargyl amines and diamines, allenyl amines and
diamines, chloroallyl diamines, lysyne analogues, referring to a
propargylamine inside a lysine side-chain, .beta.-haloamines,
R.sub.F-substituted amines, R.sub.Cl-substituted amines, and
R.sub.3Si substituted amines.
[0011] In an aspect of the invention, the compounds can be used as
selective inhibitors of amine oxidases, such as human
TPQ-containing amine oxidases (e.g., AOC.sub.1, AOC.sub.2,
AOC.sub.3, and SSAO), human LTQ-containing amine oxidases (e.g.,
LOX, LOXL, LOXL2, LOX3, and LOXL4), as well as other human copper
amine oxidases and non-mammalian copper amine oxidases.
[0012] In another aspect of the invention, the compounds can be
used as therapeutic agents for treating a number of inflammatory
conditions and diseases of connective tissue, skin, and the
gastrointestinal, central nervous system, and pulmonary systems,
including such conditions as chronic arthritis, inflammatory bowel
diseases, and chronic dermatoses. The therapeutic agents can also
be useful for treating diseases related to carbohydrate metabolism
(such as diabetes), to aberrations in adipocyte differentiation or
function or smooth muscle cell function (such as atherosclerosis
and obesity), and to various vascular diseases (such as
atheromatous and nonatheromatous arteriosclerosis, ischemic heart
disease, and peripheral arterial occlusion). The therapeutic agent
can further be used for anti-fibrotic chemotherapies, tumor
suppression, cellular senescence, developmental control, cell
motility (chemotaxis), hepatic fibrosis, Alzheimer's disease,
anti-bacterial, anti-microbial, and anti-fungal agents.
[0013] A further aspect of the present invention is to provide a
pharmaceutical composition useful for treating disorders responsive
to a increase in amine oxidase activity, containing an effective
amount of the therapeutic agent in a mixture with one or more
pharmaceutically acceptable carriers or diluents.
DETAILED DESCRIPTION
[0014] The present invention relates to compounds or therapeutic
agents that can be used as selective inhibitors of quinone
dependent copper amine oxidases, such as mammalian (e.g., human)
trihydroxyphenylalanine quinone (TPQ)-containing amine oxidases
(e.g., AOC.sub.1, AOC.sub.2, AOC.sub.3, and SSAO), LTQ-containing
amine oxidases (e.g., LOX, LOXL, LOXL2, LOX3, and LOXL4), as well
as other mammalian copper amine oxidases and non-mammalian copper
amine oxidases.
[0015] In an aspect of the invention, the therapeutic agent can
comprise a proparargylamine with the following general formula
(I):
##STR00001##
where R.sub.1 represents substituents selected from the group
consisting of hydrogen, C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24
alkenyl, C.sub.2-C.sub.24 alkynyl, C.sub.3-C.sub.20, aryl,
C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24 aralkyl, halo, silyl,
hydroxyl, sulfhydryl, C.sub.1-C.sub.24 alkoxy, C.sub.2-C.sub.24
alkenyloxy, substituted aryl, substituted alkyl, C.sub.2-C.sub.24
alkynyloxy, C.sub.5-C.sub.20 aryloxy, acyl (including
C.sub.2-C.sub.24 alkylcarbonyl (--CO-alkyl) and C.sub.6-C.sub.20
arylcarbonyl (--CO-aryl)), acyloxy (--O-acyl), C.sub.2-C.sub.24
alkoxycarbonyl (--(CO)--O-alkyl), C.sub.6-C.sub.20 aryloxycarbonyl
(--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+.dbd.C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof; or
a pharmaceutically acceptable salt thereof.
[0016] The phrase "having the formula" or "having the structure" is
not intended to be limiting and is used in the same way that the
term "comprising" is commonly used.
[0017] The term "alkyl" refers to a branched or unbranched
saturated hydrocarbon group typically although not necessarily
containing 1 to about 24 carbon atoms, such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and
the like, as well as cycloalkyl groups, such as cyclopentyl,
cyclohexyl, and the like. Generally, although again not
necessarily, alkyl groups herein contain 1 to about 18 carbon
atoms, preferably 1 to about 12 carbon atoms. The term "lower
alkyl" intends an alkyl group of 1 to 6 carbon atoms. Substituents
identified as "C.sub.1-C.sub.6 alkyl" or "lower alkyl" can contain
1 to 3 carbon atoms, and more particularly such substituents can
contain 1 or 2 carbon atoms (i.e., methyl and ethyl). "Substituted
alkyl" refers to alkyl substituted with one or more substituent
groups, and the terms "heteroatom-containing alkyl" and
"heteroalkyl" refer to alkyl in which at least one carbon atom is
replaced with a heteroatom, as described in further detail infra.
If not otherwise indicated, the terms "alkyl" and "lower alkyl"
include linear, branched, cyclic, unsubstituted, substituted,
and/or heteroatom-containing alkyl or lower alkyl,
respectively.
[0018] The term "alkenyl" refers to a linear, branched or cyclic
hydrocarbon group of 2 to about 24 carbon atoms containing at least
one double bond, such as ethenyl, n-propenyl, isopropenyl,
n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl,
eicosenyl, tetracosenyl, cyclopentenyl, cyclohexenyl, cyclooctenyl,
and the like. Generally, although again not necessarily, alkenyl
groups can contain 2 to about 18 carbon atoms, and more
particularly 2 to 12 carbon atoms. The term "lower alkenyl" refers
to an alkenyl group of 2 to 6 carbon atoms, and the specific term
"cycloalkenyl" intends a cyclic alkenyl group, preferably having 5
to 8 carbon atoms. The term "substituted alkenyl" refers to alkenyl
substituted with one or more substituent groups, and the terms
"heteroatom-containing alkenyl" and "heteroalkenyl" refer to
alkenyl or heterocycloalkenyl (e.g., heterocyclohexenyl) in which
at least one carbon atom is replaced with a heteroatom. If not
otherwise indicated, the terms "alkenyl" and "lower alkenyl"
include linear, branched, cyclic, unsubstituted, substituted,
and/or heteroatom-containing alkenyl and lower alkenyl,
respectively.
[0019] The term "alkynyl" refers to a linear or branched
hydrocarbon group of 2 to 24 carbon atoms containing at least one
triple bond, such as ethynyl, n-propynyl, and the like. Generally,
although again not necessarily, alkynyl groups can contain 2 to
about 18 carbon atoms, and more particularly can contain 2 to 12
carbon atoms. The term "lower alkynyl" intends an alkynyl group of
2 to 6 carbon atoms. The term "substituted alkynyl" refers to
alkynyl substituted with one or more substituent groups, and the
terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to
alkynyl in which at least one carbon atom is replaced with a
heteroatom. If not otherwise indicated, the terms "alkynyl" and
"lower alkynyl" include linear, branched, unsubstituted,
substituted, and/or heteroatom-containing alkynyl and lower
alkynyl, respectively.
[0020] The term "alkoxy" refers to an alkyl group bound through a
single, terminal ether linkage; that is, an "alkoxy" group may be
represented as --O-alkyl where alkyl is as defined above. A "lower
alkoxy" group intends an alkoxy group containing 1 to 6 carbon
atoms, and includes, for example, methoxy, ethoxy, n-propoxy,
isopropoxy, t-butyloxy, etc. Preferred substituents identified as
"C.sub.1-C.sub.6 alkoxy" or "lower alkoxy" herein contain 1 to 3
carbon atoms, and particularly preferred such substituents contain
1 or 2 carbon atoms (i.e., methoxy and ethoxy).
[0021] The term "aryl" refers to an aromatic substituent containing
a single aromatic ring or multiple aromatic rings that are fused
together, directly linked, or indirectly linked (such that the
different aromatic rings are bound to a common group such as a
methylene or ethylene moiety). Aryl groups can contain 5 to 20
carbon atoms, and particularly preferred aryl groups can contain 5
to 14 carbon atoms. Exemplary alkyl groups contain one aromatic
ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl,
biphenyl, diphenylether, diphenylamine, benzophenone, and the like.
"Substituted aryl" refers to an aryl moiety substituted with one or
more substituent groups, and the terms "heteroatom-containing aryl"
and "heteroaryl" refer to aryl, in which at least one carbon atom
is replaced with a heteroatom, as will be described in further
detail infra. If not otherwise indicated, the term "aryl" includes
unsubstituted, substituted, and/or heteroatom-containing aromatic
substituents.
[0022] The term "aryloxy" as used herein refers to an aryl group
bound through a single, terminal ether linkage, wherein "aryl" is
as defined above. An "aryloxy" group may be represented as --O-aryl
where aryl is as defined above. Preferred aryloxy groups contain 5
to 20 carbon atoms, and particularly preferred aryloxy groups
contain 5 to 14 carbon atoms. Examples of aryloxy groups include,
without limitation, phenoxy, o-halo-phenoxy, m-halo-phenoxy,
p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy,
p-methoxy-phenoxy, 2,4-dimethoxy-phenoxy, 3,4,5-trimethoxy-phenoxy,
and the like.
[0023] The term "alkaryl" refers to an aryl group with an alkyl
substituent, and the term "aralkyl" refers to an alkyl group with
an aryl substituent, wherein "aryl" and "alkyl" are as defined
above. Exemplary aralkyl groups contain 6 to 24 carbon atoms, and
particularly preferred aralkyl groups contain 6 to 16 carbon atoms.
Examples of aralkyl groups include, without limitation, benzyl,
2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl,
4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl,
4-benzylcyclohexylmethyl, and the like. Alkaryl groups include, for
example, p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl,
2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl,
3-ethyl-cyclopenta-1,4-diene, and the like.
[0024] The term "cyclic" refers to alicyclic or aromatic
substituents that may or may not be substituted and/or heteroatom
containing, and that may be monocyclic, bicyclic, or
polycyclic.
[0025] The terms "halo" and "halogen" are used in the conventional
sense to refer to a chloro, bromo, fluoro or iodo substituent.
[0026] The term "heteroatom-containing" as in a
"heteroatom-containing alkyl group" (also termed a "heteroalkyl"
group) or a "heteroatom-containing aryl group" (also termed a
"heteroaryl" group) refers to a molecule, linkage or substituent in
which one or more carbon atoms are replaced with an atom other than
carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon,
typically nitrogen, oxygen or sulfur. Similarly, the term
"heteroalkyl" refers to an alkyl substituent that is
heteroatom-containing, the term "heterocyclic" refers to a cyclic
substituent that is heteroatom-containing, the terms "heteroaryl"
and heteroaromatic" respectively refer to "aryl" and "aromatic"
substituents that are heteroatom-containing, and the like. Examples
of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted
alkyl, N-alkylated amino alkyl, and the like. Examples of
heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl,
quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl,
tetrazolyl, etc., and examples of heteroatom-containing alicyclic
groups are pyrrolidino, morpholino, piperazino, piperidino,
etc.
[0027] "Hydrocarbyl" refers to univalent hydrocarbyl radicals
containing 1 to about 30 carbon atoms, preferably 1 to about 24
carbon atoms, more preferably 1 to about 18 carbon atoms, most
preferably about 1 to 12 carbon atoms, including linear, branched,
cyclic, saturated, and unsaturated species, such as alkyl groups,
alkenyl groups, aryl groups, and the like. "Substituted
hydrocarbyl" refers to hydrocarbyl substituted with one or more
substituent groups, and the term "heteroatom-containing
hydrocarbyl" refers to hydrocarbyl in which at least one carbon
atom is replaced with a heteroatom. Unless otherwise indicated, the
term "hydrocarbyl" is to be interpreted as including substituted
and/or heteroatom-containing hydrocarbyl moieties.
[0028] By "substituted" as in "substituted aryl," "substituted
aryl," and the like, as alluded to in some of the aforementioned
definitions, is meant that in the alkyl, aryl, or other moiety, at
least one hydrogen atom bound to a carbon (or other) atom is
replaced with one or more non-hydrogen substituents. Examples of
such substituents include, without limitation: functional groups
such as halo, hydroxyl, silyyl, sulfhydryl, C.sub.1-C.sub.24
alkoxy, C.sub.2-C.sub.24 alkenyloxy, C.sub.2-C.sub.24 alkynyloxy,
C.sub.5-C.sub.20 aryloxy, acyl (including C.sub.2-C.sub.24
alkylcarbonyl (--CO-alkyl) and C.sub.6-C.sub.20 alkylcarbonyl
(--CO-aryl)), acyloxy (--O-acyl), C.sub.2-C.sub.24 alkoxycarbonyl
(--(CO)--O-alkyl), C.sub.6-C.sub.20 aryloxycarbonyl
(--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.4 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--ON.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N .sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R=hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.1-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, etc.), arylimino (--CR.dbd.N(alkyl), where
R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), and phosphino (--PH.sub.2); and the hydrocarbyl
moieties C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl,
C.sub.2-C.sub.24 alkyl, C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24
alkaryl, and C.sub.6-C.sub.24 aralkyl.
[0029] In addition, the aforementioned functional groups may, if a
particular group permits, be further substituted with one or more
additional functional groups or with one or more hydrocarbyl
moieties such as those specifically enumerated above. Analogously,
the above-mentioned hydrocarbyl moieties may be further substituted
with one or more functional groups or additional hydrocarbyl
moieties such as those specifically enumerated.
[0030] When the term "substituted" appears prior to a list of
possible substituted groups, it is intended that the term apply to
every member of that group. For example, the phrase "substituted
alkyl, alkenyl, and aryl" is to be interpreted as "substituted
alkyl, substituted alkenyl, and substituted aryl." Analogously,
when the term "heteroatom-containing" appears prior to a list of
possible heteroatom-containing groups, it is intended that the term
apply to every member of that group. For example, the phrase
"heteroatom-containing alkyl, alkenyl, and aryl" is to be
interpreted as "heteroatom-containing alkyl, substituted alkenyl,
and substituted aryl.
[0031] "Optional" or "optionally" means that the subsequently
described circumstance may or may not occur, so that the
description includes instances where the circumstance occurs and
instances where it does not. For example, the phrase "optionally
substituted" means that a non-hydrogen substituent may or may not
be present on a given atom, and, thus, the description includes
structures wherein a non-hydrogen substituent is present and
structures wherein a non-hydrogen substituent is not present.
[0032] When referring to a compound of the invention, applicants
intend the term "compound" to encompass not only the specified
molecular entity but also its pharmaceutically acceptable,
pharmacologically active analogs, including, but not limited to,
salts, esters, amides, prodrugs, conjugates, active metabolites,
and other such derivatives, analogs, and related compounds.
[0033] By "pharmaceutically acceptable" is meant a material that is
not biologically or otherwise undesirable, i.e., the material may
be incorporated into a pharmaceutical composition administered to a
patient without causing any undesirable biological effects or
interacting in a deleterious manner with any of the other
components of the composition in which it is contained. When the
term "pharmaceutically acceptable" is used to refer to a
pharmaceutical carrier or excipient, it is implied that the carrier
or excipient has met the required standards of toxicological and
manufacturing testing or that it is included on the Inactive
Ingredient Guide prepared by the U.S. Food and Drug administration.
"Pharmacologically active" (or simply "active") as in a
"pharmacologically active" derivative or analog, refers to a
derivative or analog having the same type of pharmacological
activity as the parent compound and approximately equivalent in
degree.
[0034] Some of the compounds disclosed herein may contain one or
more asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms. The present
invention is also meant to encompass racemic mixtures, resolved
forms and mixtures thereof, as well as the individual enantiomers
that may be separated according to methods that are well know to
those of ordinary skill in the art. When the compounds described
herein contain olefinic double bonds or other centers of geometric
asymmetry, and unless specified otherwise, it is intended to
include both E and Z geometric isomers.
[0035] As used herein, the term "stereoisomers" is a general term
for all isomers of individual molecules that differ only in the
orientation of their atoms in space. It includes enantiomers and
isomers of compounds with more than one chiral center that are not
mirror images of one another (diastereomers).
[0036] The term "asymmetric center" or "chiral center" refers to a
carbon atom to which four different groups are attached.
[0037] The term "enantiomer" or "enantiomeric" refers to a molecule
that is nonsuperimposeable on its mirror image and hence optically
active wherein the enantiomer rotates the plane of polarized light
in one direction and its minor image rotates the plane of polarized
light in the opposite direction.
[0038] The term "racemic" refers to a mixture of equal parts of
enantiomers and which is optically inactive.
[0039] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule. The phrase "enantiomeric excess" refers to a mixture
wherein one enantiomer is present is a greater concentration than
its mirror image molecule.
[0040] In one subclass of propargylamines, the therapeutic agent
can be a simple propargylamine. Examples of simple propargylamines
can include:
##STR00002##
[0041] In another subclass of propargylamines, the therapeutic
agent can be a triple bond conjugated propargylamine. Examples of
triple bond conjugated propargylamines can include:
##STR00003##
[0042] In a further subclass propargylamines, the therapeutic agent
can be a triaklylsilyl substituted propargylamines. Trialkylsilyl
substituted propargylamines can act as potential prodrugs. The
acetylenyl-Si bond can hydrolyze to release propargylamine or
conjugated propargylamine. Examples of trialkylsilyl substituted
propargylamines can include:
##STR00004##
[0043] In accordance with another aspect, the therapeutic agent can
comprise a polyproparargylamine with the following general formula
(II):
##STR00005##
where n=1, 2, or 3, and R.sub.2 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24
alkenyl, C.sub.2-C.sub.24 alkynyl, C.sub.3-C.sub.20 aryl,
C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24 aralkyl, substituted
aryl, substituted alkyl, halo, hydroxyl, sulfhydryl,
C.sub.1-C.sub.24 alkoxy, C.sub.2-C.sub.24 alkenyloxy,
C.sub.2-C.sub.24 alkynyloxy, C.sub.5-C.sub.20 aryloxy, acyl
(including C.sub.2-C.sub.24 alkylcarbonyl (--CO-alkyl) and
C.sub.6-C.sub.20 arylcarbonyl (--CO-aryl)), acyloxy (--O-acyl),
C.sub.2-C.sub.24 alkoxycarbonyl (--(CO)--O-alkyl), C.sub.6-C.sub.20
aryloxycarbonyl (--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof, or
a pharmaceutically acceptable salt thereof.
[0044] In a subclass of polypropargylamines, n=1, 2, or 3 and
R.sub.2 is selected from the group consisting of H, CH.sub.3, and
PhCH.sub.2. Examples of polypropargylamines of this subclass can
include:
##STR00006##
[0045] In accordance with a further aspect, the therapeutic agent
can comprise a homopropargylamine with the following general
formula (III):
##STR00007##
where R.sub.3, R.sub.4, and R.sub.5 can each be individually
selected from the group consisting of hydrogen, C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, C.sub.2-C.sub.24 alkynyl,
C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, substituted aryl, substituted alkyl, halo, hydroxyl,
sulfhydryl, C.sub.1-C.sub.24 alkoxy, C.sub.2-C.sub.24 alkenyloxy,
C.sub.2-C.sub.24 alkynyloxy, C.sub.5-C.sub.20 aryloxy, acyl
(including C.sub.2-C.sub.24 alkylcarbonyl (--CO-alkyl) and
C.sub.6-C.sub.20 arylcarbonyl (--CO-aryl)), acyloxy (--O-acyl),
C.sub.2-C.sub.24 alkoxycarbonyl (--(CO)--O-alkyl), C.sub.6-C.sub.20
aryloxycarbonyl (--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--N--H.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)-NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphionato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof; or
a pharmaceutically acceptable salt thereof.
[0046] In a subclass of homopropargylamines, R.sub.3 can be
selected from the group consisting of H, alkyl, aryl, halo, and
cyano, and R.sub.4 and R.sub.5 can be each be independently
selected from the group consisting of H, alkyl, and aryl. Examples
of homopropargylamines of this subclass can include:
##STR00008##
[0047] In accordance with a further aspect, the therapeutic agent
can comprise a 4-R.sub.6X.sub.1-substituted 2-butynylamine with the
following general formula (IV):
##STR00009##
where X.sub.1 is selected from the group consisting of O, S, and
C(.dbd.O)NH, and where R.sub.6 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24
alkenyl, C.sub.2-C.sub.24 alkynyl, C.sub.3-C.sub.20 aryl,
C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24 aralkyl, substituted
aryl, substituted alkyl, halo, hydroxyl, sulfhydryl,
C.sub.1-C.sub.24 alkoxy, C.sub.2-C.sub.24 alkenyloxy,
C.sub.2-C.sub.24 alkynyloxy, C.sub.5-C.sub.20 aryloxy, acyl
(including C.sub.2-C.sub.24 alkylcarbonyl (--CO-alkyl) and
C.sub.6-C.sub.20 arylcarbonyl-(--CO-aryl)), acyloxy (--O-acyl),
C.sub.2-C.sub.24 alkoxycarbonyl (--(CO)--O-alkyl), C.sub.6-C.sub.20
aryloxycarbonyl (--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato (--SO.sub.2--O,
C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl; also termed
"alkylthio"), arylsulfanyl (--S-aryl; also termed "arylthio"),
C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl), C.sub.1-C.sub.20
arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24 alkylsulfonyl
(--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof; or
a pharmaceutically acceptable salt thereof.
[0048] In a subclass of 4-R.sub.6X.sub.1-substituted
2-butynylamine, R.sub.6 can be selected from the group consisting
of H, alkyl, and aryl, and X.sub.1 can be selected from the group
consisting of O and S. Examples of 4-R.sub.6X.sub.1-substituted
2-butynylamine of this subclass can include:
##STR00010##
[0049] In another subclass of 4-R.sub.6X.sub.1-substituted
2-butynylamines, X.sub.1 can be C(.dbd.O)NH. Examples of
4-R6X.sub.1-substituted 2-butynylamine of this subclass can
include:
##STR00011##
[0050] In accordance with yet another aspect, the therapeutic agent
can comprise a 2- and 3-substituted halloallylamines with the
following general formula (V):
##STR00012##
where R.sub.7, Y.sub.1, and X.sub.2 can each be individually
selected from the group consisting of hydrogen, C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, C.sub.2-C.sub.24 alkynyl,
C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, substituted aryl, substituted alkyl, halo, hydroxyl,
sulfhydryl, C.sub.1-C.sub.24 alkoxy, C.sub.2-C.sub.24 alkenyloxy,
C.sub.2-C.sub.24 alkynyloxy, C.sub.5-C.sub.20 aryloxy, acyl
(including C.sub.2-C.sub.24 alkylcarbonyl (--CO-alkyl) and
C.sub.6-C.sub.20 arylcarbonyl (--CO-alkyl)), acyloxy (--O-acyl),
C.sub.2-C.sub.24 alkoxycarbonyl (--(CO)--O-alkyl), C.sub.6-C.sub.20
aryloxycarbonyl (--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof; or
a pharmaceutically acceptable salt thereof.
[0051] In a subclass of 2- and 3-substituted halloallylamine, the
therapeutic agent can be a simple 3-chloroallylamine. Examples of
3-chloroallylamines of this subclass can include:
##STR00013##
[0052] In another subclass of 2- and 3-substituted
halloallylamines, the therapeutic agent can be
3-(alkoxycarbonyl)-3-chloroallylamines. Examples of
3-chloroallylamines of this subclass can include:
##STR00014##
[0053] In further subclass of 2- and 3-substituted
halloallylamines, the therapeutic agent can be a
2-phenyl-3-haloallylamine. Examples of 2-phenyl-3-haloallylamines
of this subclass can include:
##STR00015##
[0054] In yet a further subclass of 2- and 3-substituted
halloallylamines, the therapeutic agent can be a
3-bromo-2-methylallylamine. Examples of 3-bromo-2-methylallylamines
of this subclass can include:
##STR00016##
[0055] In another subclass of 2- and 3-substituted halloallylamine,
the therapeutic agent can be a 2-chloroallylamine. Examples of
2-chloroallylamines of this subclass can include:
##STR00017##
[0056] In accordance with yet another aspect, the therapeutic agent
can comprise an allenyl amine with the following general formula
(VI):
##STR00018##
where R.sub.8 and R.sub.9 can each be individually selected from
the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, C.sub.2-C.sub.24 alkynyl,
C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, substituted aryl, substituted alkyl, halo, hydroxyl,
sulfhydryl, C.sub.1-C.sub.24 alkoxy, C.sub.2-C.sub.24 alkenyloxy,
C.sub.2-C.sub.24 alkynyloxy, C.sub.5-C.sub.20 aryloxy, acyl
(including C.sub.2-C.sub.24 alkylcarbonyl (--CO-alkyl) and
C.sub.6-C.sub.20 arylcarbonyl (--CO-aryl)), acyloxy (--O-acyl),
C.sub.2-C.sub.24 alkoxycarbonyl (--(CO)--O-alkyl), C.sub.6-C.sub.20
aryloxycarbonyl (--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)-NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-).sub.2),
phospho (--PO.sub.2), phosphino (--PH.sub.2), and combinations
thereof; or a pharmaceutically acceptable salt thereof.
[0057] In a subclass of allenyl amines, R.sub.8 can be selected
from the group consisting of H, alkyl, and aryl, and X.sub.3
substituted alkyl (X.sub.3=0 or N) and R.sub.9 can be selected from
the group consisting of H, alkyl, and aryl. Examples of allenyl
amines of this subclass can include:
##STR00019##
[0058] In accordance with yet another aspect, the therapeutic agent
can comprise a pyrroline derivative with the following general
formula (VII):
##STR00020##
where R.sub.10 can be selected from the group consisting of
hydrogen, C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl,
C.sub.2-C.sub.24 alkynyl, C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24
alkaryl, C.sub.6-C.sub.24 aralkyl, substituted aryl, substituted
alkyl, halo, hydroxyl, sulfhydryl, C.sub.1-C.sub.24 alkoxy,
C.sub.2-C.sub.24 alkenyloxy, C.sub.2-C.sub.24 alkynyloxy,
C.sub.5-C.sub.20 aryloxy, acyl (including C.sub.2-C.sub.24
alkylcarbonyl (--CO-alkyl) and C.sub.6-C.sub.20 arylcarbonyl
(--CO-aryl)), acyloxy (--O-acyl), C.sub.2-C.sub.24 alkoxycarbonyl
(--(CO)--O-alkyl), C.sub.6-C.sub.20 aryloxycarbonyl
(--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
alkyl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), substituted aryl and
combinations thereof; or a pharmaceutically acceptable salt
thereof.
[0059] In a subclass of pyrroline derivatives, R.sub.10 can be an
aryl or heterocyclic aryl. Examples of pyrolline of this subclass
can include:
##STR00021##
[0060] In accordance with yet a further aspect, the therapeutic
agent can comprise a chlorinated homoallylamine, such as:
##STR00022##
[0061] In accordance with another aspect, the therapeutic agent can
comprise a cycloalkenyl branched primary amine, such as:
##STR00023##
[0062] In accordance with yet another aspect, the therapeutic agent
can comprise a diamine with the following general formula (VIII) or
(IX).
##STR00024##
where m and n are each independently 1 or 2, X.sub.4 is a halo
selected from the group consisting of Cl, Br, I, and F, and R
.sub.1, R.sub.12, R.sub.13, and R.sub.14 are each independently
selected from group consisting of hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, C.sub.2-C.sub.24 alkynyl,
C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, substituted aryl, substituted alkyl, halo, hydroxyl,
sulfhydryl, C.sub.1-C.sub.24 alkoxy, C.sub.2-C.sub.24 alkenyloxy,
C.sub.2-C.sub.24 alkynyloxy, C.sub.5-C.sub.20 aryloxy, acyl
(including C.sub.2-C.sub.24 alkylcarbonyl (--CO-alkyl) and
C.sub.6-C.sub.20 arylcarbonyl (--CO-aryl)), acyloxy (--O-acyl),
C.sub.2-C.sub.24 alkoxycarbonyl (--(CO)--O-alkyl), C.sub.6-C.sub.20
aryloxycarbonyl (--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--NH.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--S0.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof; or
a pharmaceutically acceptable salt thereof.
[0063] In a subclass of diamines, the therapeutic agent can be a
propargyl, homopropargyl, allenyl, or chlorovinyl, such as where
R.sub.11 and R.sub.12 are each independently selected from the
group consisting of Ph, Bz, PhCH.sub.2CH.sub.2, Me, and H, and
R.sub.13 and R.sub.14 are each independently selected from group
consisting of Me and H. Examples of diamines of this subclass can
include:
##STR00025##
[0064] In accordance with yet another aspect, the therapeutic agent
can comprise a lysyne analogue with the following general
formula:
##STR00026##
where n is 1 or 2 and R.sub.1 is selected from group consisting of
hydrogen, C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl,
C.sub.2-C.sub.24 alkynyl, C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24
alkaryl, C.sub.6-C.sub.24 aralkyl, substituted aryl, substituted
alkyl, halo, hydroxyl, sulfhydryl, C.sub.1-C.sub.24 alkoxy,
C.sub.2-C.sub.24 alkenyloxy, C.sub.2-C.sub.24 alkynyloxy,
C.sub.5-C.sub.20 aryloxy, acyl (including C.sub.2-C.sub.24
alkylcarbonyl (--CO-alkyl) and C.sub.6-C.sub.20 arylcarbonyl
(--CO-aryl)), acyloxy (--O-acyl), C.sub.2-C.sub.24 alkoxycarbonyl
(--(CO)--O-alkyl), C.sub.6-C.sub.20 aryloxycarbonyl
(--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.2O arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)-NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--N--H.sub.2), cyano(--CN), isocyano
(--N.sup.+C.sup.-), cyanato (--O--CN), isocyanato
(--O--N.sup.+C.sup.-), isothiocyanato (--S--CN), azido
(--N.dbd.N.sup.+.dbd.N.sup.-), formyl (--(CO)--H), thioformyl
(--(CS)--H), amino (--N--H.sub.2), mono- and di-(C.sub.1-C.sub.24
alkyl)-substituted amino, mono- and di-(C.sub.5-C.sub.20
aryl)-substituted amino, C.sub.2-C.sub.24 alkylamido
(--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido (--NH--(CO)-aryl),
imino (--CR.dbd.NH where R is hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, etc.), alkylimino (--CR.dbd.N(alkyl), where R=hydrogen,
alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (--CR.dbd.N(aryl),
where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2),
nitroso (--NO), sulfo (--SO.sub.2--OH), sulfonato
(--SO.sub.2--O.sup.-), C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl;
also termed "alkylthio"), arylsulfanyl (--S-aryl; also termed
"arylthio"), C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl),
C.sub.5-C.sub.20 arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24
alkylsulfonyl (--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof; or
a pharmaceutically acceptable salt thereof.
[0065] In subclass of lysyne analogues, the therapeutic agent can
have the following general formula:
##STR00027##
where n is 1 or 2 and R.sub.15 and R.sub.16 are each independently
selected from group consisting of hydrogen, C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, C.sub.2-C.sub.24 alkynyl,
C.sub.3-C.sub.20 aryl, C.sub.6-C.sub.24 alkaryl, C.sub.6-C.sub.24
aralkyl, substituted aryl, substituted alkyl, halo, hydroxyl,
sulfhydryl, C.sub.1-C.sub.24 alkoxy, C.sub.2-C.sub.24 alkenyloxy,
C.sub.2-C.sub.24 alkynyloxy, C.sub.5-C.sub.20 aryloxy, acyl
(including C.sub.2-C.sub.24 alkylcarbonyl (--CO-alkyl) and
CO--C.sub.20 arylcarbonyl (--CO-aryl)), acyloxy (--O-acyl),
C.sub.2-C.sub.24 alkoxycarbonyl (--(CO)--O-alkyl), C.sub.6-C.sub.20
aryloxycarbonyl (--(CO)--O-aryl), C.sub.2-C.sub.24 alkylcarbonato
(--O--(CO)--O-alkyl), C.sub.6-C.sub.20 arylcarbonato
(--O--(CO)--O-aryl), carboxy (--COOH), carboxylato (--COO.sup.-),
carbamoyl (--(CO)--NH.sub.2), mono-(C.sub.1-C.sub.24
alkyl)-substituted carbamoyl (--(CO)--NH(C.sub.1-C.sub.24 alkyl)),
di-(C.sub.1-C.sub.24 alkyl)-substituted carbamoyl
(--(CO)--N(C.sub.1-C.sub.24 alkyl).sub.2), mono-substituted
arylcarbamoyl (--(CO)--NH-aryl), thiocarbamoyl (--(CS)--NH.sub.2),
carbamido (--NH--(CO)--NH.sub.2), cyano(--CN), isocyano
(--N.sup.+C), cyanato (--O--CN), isocyanato (--O--NC.sup.-),
isothiocyanato (--S--CN), azido (--N.dbd.N.sup.+.dbd.N.sup.-),
formyl (--(CO)--H), thioformyl (--(CS)--H), amino (--NH.sub.2),
mono- and di-(C.sub.1-C.sub.24 alkyl)-substituted amino, mono- and
di-(C.sub.5-C.sub.20 aryl)-substituted amino, C.sub.2-C.sub.24
alkylamido (--NH--(CO)-alkyl), C.sub.6-C.sub.20 arylamido
(--NH--(CO)-aryl), imino (--CR.dbd.NH where R is hydrogen,
C.sub.1-C.sub.24 alkyl, C.sub.5-C.sub.20 aryl, C.sub.6-C.sub.24
alkaryl, C.sub.6-C.sub.24 aralkyl, etc.), alkylimino
(--CR.dbd.N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl,
aralkyl, etc.), arylimino (--CR.dbd.N(aryl), where R=hydrogen,
alkyl, aryl, alkaryl, etc.), nitro (--NO.sub.2), nitroso (--NO),
sulfo (--SO.sub.2--OH), sulfonato (--SO.sub.2--O.sup.-),
C.sub.1-C.sub.24 alkylsulfanyl (--S-alkyl; also termed
"alkylthio"), arylsulfanyl (--S-aryl; also termed "arylthio"),
C.sub.1-C.sub.24 alkylsulfinyl (--(SO)-alkyl), C.sub.5-C.sub.20
arylsulfinyl (--(SO)-aryl), C.sub.1-C.sub.24 alkylsulfonyl
(--SO.sub.2-alkyl), C.sub.5-C.sub.20 arylsulfonyl
(--SO.sub.2-aryl), phosphono (--P(O)(OH).sub.2), phosphonato
(--P(O)(O.sup.-).sub.2), phosphinato (--P(O)(O.sup.-)), phospho
(--PO.sub.2), phosphino (--PH.sub.2), and combinations thereof, or
a pharmaceutically acceptable salt thereof.
[0066] In a subclass of lysyne analogues, R.sub.15 and R.sub.16 can
each be independently selected from group consisting of H, alkyl,
and substituted alkyls. Examples of lysyne of this subclass can
include:
##STR00028##
[0067] In accordance with another aspect, the therapeutic agent can
comprise a .beta.-haloamine, such as:
##STR00029##
[0068] In accordance with yet another aspect, the therapeutic agent
can comprise a R.sub.F, R.sub.Cl, and R.sub.3Si substituted amine
such as:
##STR00030##
[0069] The therapeutic agents described above can be used for
treatment of a disease or condition in a human where selective
inhibition of amine oxidases, such as human TPQ-containing amine
oxidases (AOC.sub.1, AOC.sub.2, and AOC.sub.3), human
LTQ-containing amine oxidases (e.g., LOX, LOXL, LOXL2, LOX3, and
LOXL4), as well as other human copper amine oxidases and
non-mammalian copper amine oxidases, is beneficial. The present
invention therefore provides a method of treating diseases by
selectively inhibiting amine oxidase activity, which method
comprises administering to an animal in need thereof a
therapeutically effective amount of a therapeutic agent or compound
in accordance with the present invention, wherein one or more
compounds or therapeutic agents are administered in association
with one or more non-toxic, pharmaceutically acceptable carriers
and/or diluents and/or adjuvants and if desired other active
ingredients.
[0070] The compounds or therapeutic agents in accordance with the
present invention can be used to treat inflammatory conditions and
diseases including but not limited to connective tissue
inflammatory conditions and diseases such as ankylosing
spondylitis, Reiter's syndrome, psoriatic arthritis, osteoarthritis
or degenerative joint disease, rheumatoid arthritis, Sjogren's
syndrome, Behget's syndrome, relapsing polychondritis, systemic
lupus erythematosus, discoid lupus erythematosus, systemic
sclerosis, eosinophilic fasciitis, polymyositis and
dermatomyositis, polymyalgia rheumatica, vasculitis, temporal
arteritis, polyarteritis nodosa, Wegener's granulomatosis, mixed
connective tissue disease, and juvenile rheumatoid arthritis;
gastrointestinal inflammatory conditions and diseases such as
Crohn's disease, ulcerative colitis, irritable bowel syndrome
(spastic colon), fibrotic conditions of the liver, inflammation of
the oral mucosa (stomatitis), and recurrent aphtous stomatitis;
central nervous system inflammatory conditions and diseases such as
multiple sclerosis, Alzheimer's disease, and ischaemia-reperfusion
injury associated with ischemic stroke; pulmonary inflammatory
conditions and diseases such as asthma, chronic obstructive
pulmonary disease, and adult respiratory distress syndrome; and
skin inflammatory conditions and diseases such as contact
dermatitis, atopic dermatitis, psoriasis, pityriasis rosea, lichen
planus, and pityriasis rubra pilaris.
[0071] Moreover, the therapeutic agents of the invention can be
used to treat diseases related to carbohydrate metabolism and
complications thereof, such as diabetes and complications of
diabetes including, but not limited to microvascular and
macrovascular disease such as atherosclerosis, vascular
retinopathies, retinopathy, nephropathy and nephrotic syndrome,
neuropathies such as polyneuropathy, mononeuropathies, and
autonomic neuropathy, and foot ulcers and joint problems, as well
as increased risk of infection; diseases related to or caused by
aberrations in adipocyte differentiation or function such as
atherosclerosis and obesity; and vascular diseases such as
atheromatous and nonatheromatous ateriosclerosis, ischemic heart
disease including myocardial infarction, peripheral aterial
occlusion, thromboangiitis obliterans (Buerger's disease), and
Raynaud's disease and phenomenon.
[0072] In particular, the present compounds can be used to treat
atherosclerosis. It is known that AOC.sub.3 (HVAP-1) is expressed
on adipocytes, smooth muscle cells, endothelial cells and is
related to inflammation. Atherosclerotic plaque consists of
accumulated intracellular and extracellular lipids, smooth muscle
cells, connective tissue, and glycosaminoglycans. The earliest
detectable lesion of atherosclerosis is the fatty streak
(consisting of lipid-laden foam cells, which are macrophages that
have migrated as monocytes from the circulation into the
subendothelial layer of the intima), which later evolves into the
fibrous plaque (consisting of intimal smooth muscle cells
surrounded by connective tissue and intracellular and extracellular
lipids).
[0073] The term "treat inflammation" is intended to include the
administration of therapeutic agents of the present invention to a
subject for purposes, which can include prophylaxis, amelioration,
prevention or cure of an inflammatory condition or disease. Such
treatment need not necessarily completely ameliorate the
inflammatory condition or disease. Further, such treatment can be
used in conjunction with other traditional treatments for reducing
the inflammatory condition known to those of skill in the art.
[0074] In addition, as noted above, LOX is responsible for the
lysine-derived cross-links in collagen and elastin, which is the
essential step for biogenesis and repair of the fibrillar
extracellular matrix. Despite what should be a harmful effect of
lysyl oxidase inhibition early in life, there is growing evidence
that the enzyme also plays a role in late-onset fibrotic conditions
in man. Thus, selective inhibitors can be viewed as potential leads
to development of anti-fibrotic chemotherapies.
[0075] Moreover, in addition to its essential role in connective
tissue maturation, several new functions, as varied as tumor
suppression, cellular senescence, developmental control, and cell
motility (chemotaxis) have been described. Abnormal LOX activity
contributes to a number of different diseases including
atherosclerosis, aortic aneurysms, pulmonary fibrosis, and hepatic
fibrosis. Also, LOX activity is increased in dementia, with
LOX-positive plaques being particularly increased Alzheimer's
disease, suggesting that LOX in the extracellular matrix may be
associated with plaque formation. Mammalian LOX has been shovel to
translocate to the nuclei of smooth muscle cells and regulate
chromatin structure and transcription. Selective inhibitors allow
for crucial breakthroughs in identifying possible tissue-specific
function of these enzymes.
[0076] Moreover, copper amine oxidases are ubiquitous in nature,
and there is a possibility that certain bacterial or fungal CAOs
may be crucial to their survival. Selective inhibitors of these
enzymes can become therapeutic agents in man as anti-bacterial,
anti-microbial, or anti-fungal agents.
[0077] The therapeutic agents can be provided in the form of
pharmaceutical compositions. The pharmaceutical compositions of the
present invention can be administered to any animal that can
experience the beneficial effects of the compounds of the
invention. Foremost among such animals are humans although the
invention is not intended to be so limited.
[0078] The pharmaceutical compositions of the present invention can
be administered by any means that achieve their intended purpose.
For example, administration can be by parenteral, subcutaneous,
intravenous, intraarticular, intrathecal, intramuscular,
intraperitoneal, or intradermal injections, or by transdermal,
buccal, oromucosal, ocular routes or via inhalation. Alternatively,
or concurrently, administration can be by the oral route.
Particularly preferred is oral administration. The dosage
administered will be dependent upon the age, health, and weight of
the recipient, kind of concurrent treatment, if any, frequency of
treatment, and the nature of the effect desired.
[0079] In addition to the pharmacologically active compounds, the
pharmaceutical preparations of the compounds can contain suitable
pharmaceutically acceptable carriers comprising excipients and
auxiliaries that facilitate processing of the active compounds into
preparations that can be used pharmaceutically. The pharmaceutical
preparations of the present invention are manufactured in a manner
that is, itself, known, for example, by means of conventional
mixing, granulating, dragee-making, dissolving, or lyophilizing
processes. Thus, pharmaceutical preparations for oral use can be
obtained by combining the active compounds with solid excipients,
optionally grinding the resulting mixture and processing the
mixture of granules, after adding suitable auxiliaries, if desired
or necessary, to obtain tablets or dragee cores.
[0080] Suitable excipients are, in particular, fillers such as
saccharides, for example, lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example,
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders, such as starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents can be added, such as the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example silica, talc, stearic acid or salts
thereof, such as magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings, that, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions can be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol, and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations, such as acetylcellulose phthalate or
hydroxypropylmethylcellulose phthalate, are used. Slow-release and
prolonged-release formulations may be used with particular
excipients such as methacrylic acid--ethylacrylate copolymers,
methacrylic acid--ethyl acrylate copolymers, methacrylic
acid--methyl methacrylate copolymers and methacrylic acid--methyl
methylacrylate copolymers. Dye stuffs or pigments can be added to
the tablets or dragee coatings, for example, for identification or
in order to characterize combinations of active compound doses.
[0081] Other pharmaceutical preparations that can be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer such as glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules that may be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids such as fatty oils or liquid
paraffin. In addition, stabilizers may be added.
[0082] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example water-soluble salts and alkaline solutions. Especially
preferred salts are maleate, fumarate, succinate, S,S tartrate, or
R,R tartrate. In addition, suspensions of the active compounds as
appropriate oily injection suspensions can be administered.
Suitable lipophilic solvents or vehicles include fatty oils, for
example, sesame oil, or synthetic fatty acid esters, for example,
ethyl oleate or triglycerides or polyethylene glycol-400 (the
compounds are soluble in PEG-400). Aqueous injection suspensions
can contain substances that increase the viscosity of the
suspension, for example sodium carboxymethyl cellulose, sorbitol,
and/or dextran. Optionally, the suspension may also contain
stabilizers.
[0083] The following examples provided are illustrative, but not
limiting, of the method and compositions of the present invention.
Other suitable modifications and adaptations of the variety of
conditions and parameters normally encountered and obvious to those
skilled in the art are within the spirit and scope of the
invention.
EXAMPLES
[0084] In the following Examples, 0.9 mL aliquots of a solution of
candidate inhibitor in 100 mM potassium phosphate buffer, pH 7.2
was mixed bovine plasma amine oxidase (0.1 mL, about 8 AM) and
incubated at 30.degree. C. aerobically. Aliquots (0.1 mL) were
periodically withdrawn using disposable calibrated Drummond
micropipettes and diluted with 1.0 mL of benzylamine (5 mM in 50 mM
sodium phosphate buffer, pH 7.2) in a 1 cm quartz cuvette (1.5 mL
volume). The rate of oxidation of benzylamine to benzaldehyde was
measured by recording the increase in absorbance at 250 nm for 1
minute and compared to the rate of benzylamine oxidation in a
companion control solution of enzyme without inhibitor. The
concentration of active BPAO was estimated from the rate of
benzylamine oxidation. Inhibitory potency values (IC.sub.50 values)
and partition values for inactivation of BPAO were measured at
various times as in indicated in the Tables. IC.sub.50 values for
lysyl oxidase (LO), arthrobacter globoformis amine oxidase (AGAO)
and pichia pastoris lysyl oxidase (PPLO) were also measured in a
similar manner.
TABLE-US-00001 TABLE 1 Inactivation of BPAO by substituted
allylamines and propargylamines 20 min IC.sub.50 partition Compound
(microM) ratio 1 ##STR00031## 1000 555 2 ##STR00032## 500 330 3
##STR00033## 700 461 4 ##STR00034## 10 6 5 ##STR00035## 13 10 6
##STR00036## 20 20 7 ##STR00037## 9 4.2 8 ##STR00038## 2000 -- 9
##STR00039## 24 29 10 ##STR00040## 2 2 11 ##STR00041## 11 6
TABLE-US-00002 TABLE 2 Inhibitory potency and partition ratios of
homopropargylamine and its analogs on bovine plasma amine oxidase
Compound IC.sub.50.sup.a (.mu.M) Partition Ratio.sup.b 1
##STR00042## 2.9 .sup.c 2 ##STR00043## 10 .sup.c 3 ##STR00044##
13.5 13 4 ##STR00045## 8.4 14 5 ##STR00046## .sup.d N.D. 6
##STR00047## 3.6 7 7 ##STR00048## 4.6 8 8.sup.e ##STR00049## 108
N.D. 9.sup.e ##STR00050## 6.5 mM N.D. 10 ##STR00051## 2.0 5
.sup.aThe number listed represents the concentration needed to
achieve 50% inactivation at the point (30 min) when the rapid phase
of activity loss reaches the plateau point. .sup.bN.D., partition
ratio not determined. .sup.c No apparent competing substrate
activity .sup.d The IC.sub.50 cannot be determined because of the
poor solubility of this compound. Enzyme lost 20% of activity at a
concentration of 0.2 mM. .sup.eCompound 8 and 9 were assayed as
racemic mixtures.
TABLE-US-00003 TABLE 3 Additional analogs designed as potential
selective lysyl oxidase (LO) inhibitors, Comparison of the
inhibitory potency of lysine derivatives for bovine plasma amine
oxidase (BPAO), LO, arthrobacter globiformis amine oxidase (AGAO),
and pichia pastoris lysyl oxidase (PPLO) ##STR00052## IC.sub.50(20
min) BPAO IC.sub.75(20 min) LO* IC.sub.50(BPAO)/IC.sub.75(LO)
IC.sub.50(30 min)AGAO IC.sub.50(30 min)PPLO R =
NHCH.sub.2CH.sub.2Ph 1.8 mM 0.45 mM 1.11 0.25 mM 0.25 mM R =
NHCH.sub.2CONHCH.sub.2COOEt 0.09 mM 0.65 mM 0.14 3.5 mM 3.0 mM R =
NEt.sub.2 10 mM 0.25 mM 40 7 .mu.M.sup.# 5.0 mM *Assay performed by
Amitha Palamakumbura and Philip Trackman, Boston University
.sup.#Determined on the basis of reversible competitive
inhibition.
TABLE-US-00004 TABLE 4 ##STR00053## R = 5 min IC.sub.50 for BPAO H
~0.5 .mu.M CH.sub.3CH.sub.2 ~0.5 .mu.M PhCH.sub.2CH.sub.2 ~0.5
.mu.M Ph (R isomer) 1.2 .mu.M Ph (S isomer) 1.1 .mu.M
* * * * *